Inhibiting the Aggregation of Aß by Natural Product Molecules.

The abnormal aggregation of Aß has been considered one of the primary causative factors for Alzheimer's disease. Diverse molecular entities have been developed to mitigate the formation of toxic Aß aggregates within the brain by inhibiting Aß aggregation. Recognizing that many FDA-approved drugs are derived from natural products, we present a summary of recent discoveries involving natural product molecules with inhibitory effects on Aß aggregation. By consolidating these findings, our review offers researchers a concise overview of the latest advancements in natural product-based interventions for Alzheimer's disease.

Recent Progress in Site-Selective Modification of Peptides and Proteins Using Macrocycles.

Peptides and proteins undergo crucial modifications to alter their physicochemical properties to expand their applications in diverse fields. Various techniques, such as unnatural amino acid incorporation, enzyme catalysis, and chemoselective methods, have been employed for site-selective peptide and protein modification. While traditional methods remain valuable, advancement in host-guest chemistry introduces innovative and promising approaches for the selective modification of peptides and proteins. Macrocycles exhibit robust binding affinities, particularly with natural amino acids, which facilitates their use in selectively binding to specific sequences. This distinctive property endows macrocycles with the potential for modification of target peptides and proteins. This review provides a comprehensive overview of strategies utilizing macrocycles for the selective modification of peptides and proteins. These strategies unlock new possibilities for constructing antibody-drug conjugates and stabilizing volatile medications.

SN2 Reaction at the Amide Nitrogen Center Enables Hydrazide Synthesis.

Nucleophilic substitutions are fundamentally important transformations in synthetic organic chemistry. Despite the substantial advances in bimolecular nucleophilic substitutions (SN2) at saturated carbon centers, analogous SN2 reaction at the amide nitrogen atom remains extremely limited. Here we report an SN2 substitution method at the amide nitrogen atom with amine nucleophiles for nitrogen-nitrogen (N-N) bond formation that leads to a novel strategy toward biologically and medicinally important hydrazide derivatives. We found the use of sulfonate-leaving groups at the amide nitrogen atom played a pivotal role in the reaction. This new N-N coupling reaction allows the use of O-tosyl hydroxamates as electrophiles and readily available amines, including acyclic aliphatic amines and saturated N-heterocycles as nucleophiles. The reaction features mild conditions, broad substrate scope (>80 examples), excellent functional group tolerability, and scalability. The method is applicable to late-stage modification of various approved drug molecules, thus enabling complex hydrazide scaffold synthesis.

Total Syntheses of Phleghenrines A and C.

Herein, we report the total syntheses of phleghenrines A and C from commercially available starting materials in 7 and 8 steps, respectively. Notable steps include an inverse electron-demand Diels-Alder reaction between a masked o-benzoquinone and a N-protected enamine to prepare one key intermediate with a bicyclo[2.2.2]octenone core, a Büchner-Curtius-Schlotterbeck one-carbon insertion to expand the bicyclo[2.2.2]octenone to a bicyclo[3.2.2]nonenone, and Trauner's modified 2-pyridone synthesis to install the 2-pyridone moiety.

Modular and practical diamination of allenes.

Vicinal diamines are privileged scaffolds in medicine, agrochemicals, catalysis, and other fields. While significant advancements have been made in diamination of olefins, diamination of allenes is only sporadically explored. Furthermore, direct incorporation of acyclic and cyclic alkyl amines onto unsaturated π systems is highly desirable and important, but problematic for many previously reported amination reactions including the diamination of olefins. Herein, we report a modular and practical diamination of allenes, which offers efficient syntheses of ß,γ-diamino carboxylates and sulfones. This reaction features broad substrate scope, excellent functional group tolerability, and scalability. Experimental and computational studies support an ionic reaction pathway initiated with a nucleophilic addition of the in situ formed iodoamine to the electron deficient allene substrate. An iodoamine activation mode via a halogen bond with a chloride ion was revealed to substantially increase the nucleophilicity of the iodoamine and lower the activation energy barrier for the nucleophilic addition step.

Concise Synthesis of (-)-GA18 Methyl Ester.

Gibberellins (GAs) are important plant hormones, but some of their family members are in extremely limited natural supply including GA18. Herein, we report a concise synthesis of (-)-GA18 methyl ester, a member of the C20 gibberellins, from commercially available and cheap andrographolide. Our synthesis features an intramolecular ene reaction to form the C ring, an oxidative cleavage followed by aldol condensation to realize a ring contraction and form the challenging trans-hydrindane (AB ring), and a photochemical [2+2] cycloaddition accompanied by a subsequent SmI2-mediated skeletal rearrangement to construct the methylenebicyclo[3.2.1]octanol moiety (CD ring).

Evaluation of resources and environmental carrying capacity of marine ranching in China: An integrated life cycle assessment-emergy analysis.

Resources and environmental carrying capacity (RECC) describes the ability of a system to achieve healthy and sustainable development. Various marine ranching enterprises have emerged in China in recent years, which have aroused concern and debate about the RECC of marine ranching systems. By taking the environmental impact calculated by life cycle assessment (LCA) into consideration in emergy analysis (EA), this study evaluated the comprehensive RECC performance of the whole system and each stage of a marine ranching system in China. The resource use efficiency (RUE) and system carrying ratio (SCR) of the system were reasonably good. However, its environmental loading ratio (ELR), emergy yield ratio (EYR), and emergy sustainability index (ESI) were unsatisfactory. First, the nonrenewable resources dominated the emergy input. Second, the emergy input from the purchased resources was much greater than that of local resources. Third, the potential environmental impact mainly came from the construction stage. Fourth, serious overload of RECC was observed in the maintenance stage. The results indicate that the system is efficient, and its RECC is in a safe state, but the system has deficiencies in environmental protection and the exploitation and utilization of local resources. The proposed analysis framework helps us comprehensively understand the marine ranching RECC performance and provides a research paradigm reference for the sustainability analysis of other complex eco-economic systems.

Bioinformatics screening of biomarkers related to liver cancer.

BACKGROUND: Liver cancer is a common malignant tumor in China, with high mortality. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, mRNA quantification and the clinical data of liver cancer. However, the hub genes, which can be served as biomarkers for diagnosis and treatment of early liver cancer, are not well screened. RESULTS: Here we present a new method for getting 6 key genes, aiming to diagnose and treat the early liver cancer. We firstly analyzed the different expression microarrays based on TCGA database, and a total of 1564 differentially expressed genes were obtained, of which 1400 were up-regulated and 164 were down-regulated. Furthermore, these differentially expressed genes were studied by using GO and KEGG enrichment analysis, a PPI network was constructed based on the STRING database, and 15 hub genes were obtained. Finally, 15 hub genes were verified by applying the survival analysis method on Oncomine database, and 6 key genes were ultimately identified, including PLK1, CDC20, CCNB2, BUB1, MAD2L1 and CCNA2. The robustness analysis of four independent data sets verifies the accuracy of the key gene's classification of the data set. CONCLUSIONS: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new method to identify the 6 key genes for diagnosis and treatment of early liver cancer, and these key genes can help us understand the pathogenesis of liver cancer more deeply.

Paternal fenvalerate exposure transgenerationally impairs cognition and hippocampus in female offspring.

The impairments of maternal fenvalerate exposure have been well documented in previous study, but little was known about the effects of paternal fenvalerate exposure. The current study aimed to assess the effects of paternal fenvalerate exposure on spatial cognition and hippocampus across generations. Adult male mice (F0) were orally administered with fenvalerate (0, 2 or 20 mg/kg) for 5 weeks. F0 males were mated with untreated-females to generate F1 generation. F1 males were mated with F1 control females to generate F2 generation. For F1 and F2 adult offspring, spatial learning and memory were detected by Morris water maze. Results showed that spatial learning and memory were impaired in F1 females but not F1 males derived from F0 males exposed to 20 mg/kg FEN. Furthermore, significant impairment of spatial learning and memory were found in F2 females but not F2 males derived from F0 males exposed to 20 mg/kg FEN. As expected, histopathology showed that neural density in hippocampal CA3 region was reduced in F1 and F2 females but not F1 and F2 males derived from F0 males exposed to 20 mg/kg FEN. Mechanistically, hippocampal thyroid hormone receptor alpha1 (TRα1) was down-regulated in F1 and F2 females derived from F0 males exposed to 20 mg/kg FEN. Correspondingly, hippocampal brain-derived neurotrophic factor, tropomyosin receptor kinase B and p75 neurotrophin receptor, three downstream genes of TR signaling, were down-regulated in F1 and F2 females. Taken together, the present study firstly found that paternal fenvalerate exposure transgenerationally impaired spatial cognition in a gender-dependent manner. Hippocampal TR signaling may, at least partially, contribute to the process of cognitive impairment induced by paternal fenvalerate exposure. Further exploration in the mode of action of fenvalerate is critically important to promote human health and environmental safety.

Flow Chemistry-Enabled Divergent and Enantioselective Total Syntheses of Massarinolin†A, Purpurolides†B, D, E, 2,3-Deoxypurpurolide†C, and Structural Revision of Massarinolin†A.

Massarinolin A and purpurolides are bioactive bergamotane sesquiterpenes condensed with a variety of synthetically challenging ring systems: a bicyclo[3.1.1]heptane, an oxaspiro[3.4]octane, and a dioxaspiro[4.4]nonane (oxaspirolactone). Herein, we report the first enantioselective total syntheses of massarinolin A, purpurolides B, D, E, and 2,3-deoxypurpurolide C. Our synthesis and computational analysis also led to a structural revision of massarinolin A. The divergent approach features an enantioselective organocatalyzed Diels-Alder reaction to install the first stereogenic center in high ee, a scalable flow photochemical Wolff rearrangement to build the key bicyclo[3.1.1]heptane, a furan oxidative cyclization to form the oxaspirolactone, a late-stage allylic C-H oxidation, and a Myers' NBSH-promoted sigmatropic elimination to install the exo methylene group of massarinolin A.

Pubertal fenvalerate exposure impairs cognitive and behavioral development partially through down-regulating hippocampal thyroid hormone receptor signaling.

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.

Enantioselective Total Synthesis of (+)-Plumisclerin†A.

The first and enantioselective total synthesis of (+)-plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring-formation protocol was adopted to generate the characteristic tricycle[4.3.1.01,5 ]decane and trans-fused dihyrdopyran moiety. Scalable enantioselective LaIII -catalyzed Michael reaction, palladium(0)-catalyzed carbonylation and SmI2 -mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D-ring system having six continuous stereogenic centers and two all-carbon quaternary centers. The trans-fused dihyrdopyran moiety with an exo side-chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)-plumisclerin A.

Antifungal agents against Aspergillus niger for rearing rice leaffolder larvae (Lepidoptera: Pyralidae) on artificial diet.

Mold contamination is an important issue in insect mass rearing. Frequently used antifungal agents such as sorbic acid and methylparaben have negative impact on many lepidopteran larvae, which might be one of the reasons for the difficulty in rearing rice leaffolder, Cnaphalocrocis medinalis (Güenée). In this study, 19 antifungal agents, including 7 food preservatives, 6 antifungal drugs, and 6 agricultural fungicides, were screened for their inhibitory activities on Aspergillus niger in diets. The results demonstrated that most of the tested chemicals are unsuitable as mold inhibitors in the diets of the rice leaffolder, and the rice leaffolder neonate is sensitive to sorbic acid and methylparaben. These two mold inhibitors at commonly used concentrations were shown to impact the survival of rice leaffolder larvae fed on artificial diets. Among the tested mold inhibitors, natamycin was the safest for the rice leaffolder larvae. Much higher larva survival was observed for the larvae fed on diets containing natamycin as an antifungal agent (59 and 72% at 200 and 400 ppm, respectively). Two agricultural fungicides, tebuconazole and azoxystrobin, are also potent as mold inhibitors when used in insect diets. The mixed use of natamycin and sorbic acid, or methylparaben, and the mixed use of sorbic acid and azoxystrobin resulted in significantly higher larva survival than sorbic acid + methylparaben. Natamycin + azoxystrobin and sorbic acid + tebuconazole resulted in larva survival similar to that of sorbic acid + methylparaben. The ternary combination of natamycin, sorbic acid, and methylparaben was the best combination for the rearing of rice leaffolder.

Resistance in Cnaphalocrocis medinalis (Lepidoptera: Pyralidae) to new chemistry insecticides.

The control of rice leaffolder, Cnaphalocrocis medinalis (Guenée), depended mainly on the insecticide application in China for a long time, and the resistance development impacted the effects of insecticide application. In this study, 13 conventional and new chemistry insecticides were assayed for the toxicities to the larvae of rice leaffolder collected from Nanning, Changsha, and Nanjing, China, with rice seedling dip method during 2011-2013. Among the tested chemicals, macrolide insecticides spinetoram, spinosad, abamectin, and emanectin benzoate have the highest toxicities, whereas monosultap and Bt have the least toxicities to this insect. Comparing with the baseline data established in 2010, the susceptibilities of rice leaffolder to chlorantraniliprole, metaflumizone, and tebufenozide are declining simultaneously and gradually in the three regions from 2011 to 2013, and C. medinalis are becoming resistance to chlorantraniliprole, metaflumizone, and tebufenozide. The synchronous decreases of susceptibility in three geographic populations were not observed for macrolide insecticides, indoxacarb, chlorpyrifos, monosultap, and Bt. The synchronous insecticide susceptibility declines in field populations of the migratory insect collected from different areas indicated resistance evolution, and the sequence application patterns of different insecticides should be scheduled to delay the further development of resistance along the migratory pathway of the rice leaffolder in China.